Identifying causal variants in suspected Mendelian disorders remains challenging when whole-genome sequencing reveals numerous rare candidates but no obvious molecular diagnosis. We developed PerGen, a pipeline that integrates family-based filtering of single-nucleotide variants, indels, structural variants, and mitochondrial variants with phenotype-driven prioritization, network analysis, and experimental validation. The pipeline integrates multiple existing tools (Seqr, Exomiser, AnnotSV, RegulomeDB, AMELIE, SpliceAI, CADD, DOMINO, dosage sensitivity metrics, and others) with custom R scripts. We applied the pipeline to whole-genome sequencing of a proband with early-onset, persistently housebound ME/CFS and three unaffected second-degree relatives. To assess whether the proband represented an atypical form of ME/CFS, his phenotype was compared with that of 9,593 participants from the EMEA Pan-European ME/CFS Survey. The proband's Local Outlier Factor exceeded the 95th percentile of the reference distribution (p = 0.043), supporting investigation as a possible Mendelian case. After filtering, 19 candidate genes remained. Prioritization against a 369-gene ME/CFS disease module identified the neuronal adhesion genes CNTN6, CNTN5, and CDH13 as the strongest candidates (nominally significant), although none remained significant after correction for multiple testing. Nevertheless, these variants deserve further investigations in this case. A previously unreported heterozygous splice-site variant in LBR (1:225411334 T>C on GRCh38) was absent from all sequenced relatives and predicted to abolish splice donor activity (SpliceAI = 0.73). Peripheral blood smear analysis demonstrated marked neutrophil hypolobulation (26% mononuclear, 68% bilobed, none with more than three lobes; n = 191), consistent with Pelger-Huët anomaly, supporting this variant as a novel pathogenic LBR allele. However, the benign nature of Pelger-Huët anomaly together with the weak network connectivity of LBR to the ME/CFS disease module suggests that this finding is incidental and unlikely to explain the patient's illness. Nevertheless, since compound heterozygous and homozygous mutations of LBR can lead to severe forms of skeletal dysplasia, this finding is relevant to genetic counseling. Although no definitive molecular diagnosis was established, this study illustrates how integrated genomic analysis, phenotype outlier detection, and network-based prioritization can be combined to investigate suspected Mendelian forms of complex diseases.